A reassessment of Jackson’s checklist and identification of two Down syndrome sub-phenotypes

Abstract

Down syndrome (DS) is characterised by several clinical features including intellectual disability (ID) and craniofacial dysmorphisms. In 1976, Jackson and coll. identified a checklist of signs for clinical diagnosis of DS; the utility of these checklists in improving the accuracy of clinical diagnosis has been recently reaffirmed, but they have rarely been revised. The purpose of this work is to reassess the characteristic phenotypic signs and their frequencies in 233 DS subjects, following Jackson's checklist. 63.77% of the subjects showed more than 12 signs while none showed less than 5, confirming the effectiveness of Jackson's checklist for the clinical diagnosis of DS. An association between three phenotypic signs emerged, allowing us to distinguish two sub-phenotypes: Brachycephaly, short and broad Hands, short Neck (BHN), which is more frequent, and "non-BHN". The strong association of these signs might be interpreted in the context of the growth defects observed in DS children suggesting decreased cell proliferation. Lastly, cognitive assessments were investigated for 114 subjects. The lack of association between the presence of a physical sign or the number of signs present in a subject and cognitive skills disproves the stereotype that physical characteristics are predictive of degree of ID.

Partial trisomy 21 with or without highly restricted-Down syndrome critical region (HR- DSCR). Report of two new cases and reanalysis of the genotype-phenotype association

“…Moreover, collection and analysis of the 25 physical signs recognized in the classic work by Jackson et al [18] as the most discriminating signs for DS diagnosis, can be a useful tool that can help clinicians in evaluation. As recently demonstrated [22], Jackson's checklist has a current validity in clinical use: individuals with 13 or more signs or with less than 5 signs can correctly be diagnosed as affected or non-affected. In the present work, subjects were therefore classi ed as DS or non-DS according to the clinical team evaluation supported by the analysis of Jackson's checklist.…”

Partial trisomy 21 with or without highly restricted Down syndrome critical region (HR-DSCR): report of two new cases and reanalysis of the genotype–phenotype association

“…Moreover, collection and analysis of the 25 physical signs recognized in the classic work by Jackson et al [ 18 ] as the most discriminating signs for DS diagnosis, can be a useful tool that can help clinicians in evaluation. As recently demonstrated [ 22 ], Jackson’s checklist has a current validity in clinical use: individuals with 13 or more signs or with less than 5 signs can correctly be diagnosed as affected or non-affected. In the present work, subjects were therefore classified as DS or non-DS according to the clinical team evaluation supported by the analysis of Jackson’s checklist.…”

Machine learning based analysis for intellectual disability in Down syndrome

“…The DS clinical dataset here reported in Supplementary Table 1 is composed of a collection of anonymized personal records regarding genetic, diagnostic, clinical, and auxological information. For details regarding the recorded data, we refer to previous works where subjects are indicated with the same DS subject code [ 11 , 18 , 30 , 31 ].…”

“…The most constant and typical features of DS are intellectual disability (ID) and craniofacial dysmorphisms, together with other variable signs and symptoms, such as cardiac malformations and growth delay [ [4] , [5] , [6] , [7] , [8] , [9] ]. In particular, ID is present to some degree of severity in virtually all individuals with DS [ 2 , 10 ] and represents the most relevant clinical symptom for which a pathogenic mechanism has not been identified yet [ 11 ].…”